EVERYTHING YOU WANTED TO KNOW

        ABOUT STEM CELLS,

 

CLONING AND GENETIC ENGINEERING


                                        BUT WERE AFRAID TO ASK.


by: JAMES TREFIL



I T WAS NOT BY CHANCE that President Bush’s first televised address, last August, 2000, was about stem cell research, coming as it did at the height of a summer swirling with heated debate over the issue (“one of the most profound of our time,” according to the President). That and other recent debates have raised questions not only about changes in science and medicine but about such profound issues as the nature and value of human life, and whether humans have the moral right to tamper with genetic material, on the one hand, or the obligation to develop technologies that would alleviate the suffering of millions, on the other. Such questions are important, but only by understanding the science involved can we begin to address the ethical conundrums coming our way.


With nearly every advance in medicine, from the smallpox vaccine to organ trans-plants, there has been controversy over how much we should be altering nature. When Louise Brown, the world’s first test-tube baby (now a healthy 23-year-old), was born in England in 1978, some people called conception out-side the body immoral and tried to have the technique banned.


Back in the 1970s, science made advances in two areas that seemed, on the surface, unrelated—but which have veered ever closer to each other. One was a growing understanding of, and ability to manipulate, deoxyribonucleic acid (DNA), the molecule that provides our genetic code. The other involved the advent of in vitro fertilization (lVF), the technology responsible for Louise Brown and nearly a million babies since.


JVF is a process by which eggs are removed surgically from a woman’s ovaries and fertilized with sperm in a laboratory. After undergoing a few cell divisions, several of the resulting embryos are inserted into a woman’s uterus where, with luck, at least one will develop into a full-term fetus. In any one trial of IFV, as many as io to 20 eggs may be extracted and fertilized, and the majority of the resulting embryos are often frozen at an early stage of development, in case they will be needed for later attempts at implantation in the uterus.


Though IVF offered new hope to many who could not otherwise conceive, it also opened up a slew of ethical questions, beginning with the status of those embryos that remain unused in the lab. Then there is the fact that the woman who donates the egg need not be the one who carries the embryo or who raises the child. It is, in fact, possible to have as many as five adults who could claim parenthood in an IVF scenario: the sperm donor, the egg donor, the woman who carries the fetus and a couple responsible for its upbringing.


Still, for all the potential issues it raises, IVF was in many ways just the beginning, a relatively simple manipulation of the natural order. The closer science has gotten to deciphering our genetic makeup, the more complicated the landscape has grown.


GENES AND DNA


BY THE MIDDLE OF THE 20TH CENTURY, scientists had begun to realize that “genes”—the name given to whatever it was that passed down inherited traits— were made of DNA and that they were located on chromosomes, threadlike struct-ures found in cell nuclei of almost all living things.


For molecular biologists, the second half of the 20th century was devoted to divining the structure of the DNA molecule (the double helix, discovered in 1953) and then figuring out how the molecule’s funda-mental components—called nucleotides—combined to form genes, how genes provided the instructions for making the molecules that allow living things to funct-ion, which genes did what, and where they were located. Just last year, scientists announced that they’d sequenced the human genome. Though they are far from figuring out what all of our genes do, they now know the order and location on our chromosomes of all of the nucleotides and have identified about half of our genes.


Much of the research on human DNA has focused on diseases that are prevalent in families or in certain ethnic groups—starting with such single-gene disorders as cystic fibrosis, Tay-Sachs disease and sickle-cell anemia—because medical histories of affected families were available and the fruits of such research might save, or at least improve, countless lives.


As our understanding of our genes has increased, so have our choices dealing with birth and conception. For several decades, couples with family histories of partic-ular diseases have sought the advice of genetic counselors about whether to have children. With amniocentesis—a procedure in which amniotic fluid is extracted from the womb and examined—expectant mothers have long been able to deter-mine if a developing fetus has certain chromosomal disorders. But more recent advances have brought the potential for couples to be advised not only on the basis of family history but on the presence of genetic markers of hereditary disease in their DNA. And with IVF technology came the ability to screen embryos for chromosomal anomalies—and for specific genetic traits, including genetic diseases.



Along with advances in screening in recent decades, there has been a surge of research on ways to treat existing genetic disorders. That research was based largely on two great truths that had been revealed about DNA. The first is that the sole function of most genes is to give cells encoded instructions for churning out particular proteins, the building blocks of life. There are tens of thousands of very different proteins in the human body—from collagen and hemoglobin to various hormones and enzymes—and each is encoded by a particular order of nucleotides in a gene . (Many diseases are caused by defective genes that don’t produce their protein correctly—and treatments that introduce missing proteins have long been used for such disorders as diabetes and hemophilia.)


The second insight is that all living things use the same basic genetic code . Just as all the books in a great library can be written in a single language, so, too, are all living things the result of different messages “written” in the same exact DNA language—and “read” by our cells. This means that if a stretch of DNA is taken from a donor and inserted into the DNA of a host’s cells, those cells will read the new message, regardless of its source.


Though there are endless possible applications for this phenomenon (and at least as many complicating factors), doctors found particularly promising the idea of fixing broken genes by manipulating DNA through a process known as gene therapy, a form of genetic engineering.


GENE THERAPY


IN SOME WAYS, MANIPULATING DNA IS A COMPLETELY NATURAL PHENOMENON. Certain kinds of viruses—including HIV and others—infect us by inserting their genetic information into our cells, which then haplessly reproduce the invading virus. In some forms of gene therapy, this kind of virus itself is engineered so that the viral gene that causes the disease and allows the virus to reproduce is removed and replaced with a healthy version of the human gene that needs “fixing.” Then this therapeutic, engineered virus is sent off to do its work on the patient’s cells. There are hundreds of procedures using such “viral vectors” in clinical trials today, targeting diseases that range from rheumatoid arth-ritis to cancer. So far there have been few, if any, real successes—and the field received a serious setback in 1999 when a patient died while undergoing gene therapy trials for liver disease.


But even if this form of gene therapy, or one like it, can be made to be safe and effective, it still represents a relatively short-term approach to genetic disease— compared with what is theoretically possible. After all, even if individuals can be successfully treated, their descendants would likely still inherit the gene or genes that caused their ailments. The form of gene therapy we’ve been discussing affects so-called somatic cells, which make up the vast majority of cells in our body. But it is not somatic cells but germ cells—our eggs and sperm—that pass our genes to our offspring.


GENETIC ENGINEERING


WHEN TALKING ABOUT CHANGING THE DNA IN HUMAN GERM CELLS, scientists use the term “germ line therapy.” But in plants or animals, it’s what we commonly think of as “genetic engineering.” Either way, it means altering the DNA of an organism in a way that increases the likelihood (or, in some cases, ensures ) that all of its off-spring will have the same, engineered,

characteristics.


So far, this form of genetic engineering has not been attempted on humans (as far as we know), but it is used on nearly every other life-form—from bacteria to plants to livestock. Virtually all insulin used to treat diabetes comes from bacteria whose DNA has been modified by the addition of the human gene for insulin, which the bacteria then produce. Plants are routinely engineered so that they will be resistant to certain pests or discases, withstand particular herbicides or grow in previously unusable soils. One area of intense debate concerns the extent to which such genetically modified organisms should be used in agriculture. In the United States, about half of the soybeans and a quarter of the corn grown on farms have been genetically modified. While the industry and many experts argue that pro-ducts that are easier to grow or contain more nutrients (or even produce pharmaceut -icals) could help prevent worldwide hunger and disease, critics question the possible side effects—particularly to the environment—of introducing new genes into agricultural products.


The truth is, ther e is still an inestimable amount that we don’t know about the functions of particular genes or how they work in tandem. Much of the concern about genetic engineering—in plants or in people—rests on this fact. Yet with the promise of tomatoes that prevent cancer, salmon many times the size of those produced in nature, even pets engineered to be nonallergenic, many people hope that similar enhancements can be made to human genes as well. After all, such techniques as genetic screening of embryos, gene therapy and genetic engineering have the potential not only to prevent disease but to increase the likelihood of desired traits—from eye color to intelligence and other attributes. (Though we’re very far from custom-designing our offspring, there are already cases of genetic screening of embryos for desired traits—including parents seeking bone-marrow matches for older, ill children.)


CLONING


THERE ARE ALSO THOSE WHO SEE GREAT PROMISE IN another form of custom-designed offspring: cloning. Though most scientists oppose human cloning, three researchers caused quite a stir earlier this year when they each, independently, announced that they were working to create human clones.


The modem age of cloning can be said to have begun in 1996, when Jan Wilmut of Roslin Institute in Scotland oversaw the birth of Dolly, the first mam-mal known to have been produced by cloning from an adult cell. Worldwide “Hello, Dolly” headlines announced the breakthrough, and subsequently, scientists working with goats, pigs, mice and cows followed in Wilmut’s path.



To “create” Dolly, Wilmut and his colleagues took an unfertilized egg from a ewe and removed its chromosomal material, replacing it with a somatic cell (replete with DNA) from another ewe. In normal fertilization, when sperm and egg merge, the resulting cell—containing all the genetic information necessary—immediately starts dividing. In cloning Dolly, the somatic cell and the egg were fused with an electric current, which somehow prompted the package to act as though it were a newly fertilized egg. The resulting embryo was inserted into the uterus of a third ewe, using the techniques that had seen such success in in vitro fertilization.


In some respects, cloning can be likened to a construction project. The egg is like a crew of workers ready to build according to the specifications on a blueprint (DNA) once the plan is finalized and the whistle blows (fertilization). Whatever the crew sees on the blueprint, it will build. In the cloning process, scientists insert an already completed blueprint and—in the form of an electric current or some other prompt—blow the whistle.


But just as independent builders using the same blueprint can build —slightly diff-erent structures, so cloning does not create absolute replicas. Though a newborn clone will have chromosomal DNA identical to that of the adult donor and in that way would be the adult’s genetic twin, it would also be a twin developed as a fetus in a different womb, flooded with a different bath of chemicals at different points in its development, born decades later and raised in a different environment. The clone could also differ from the donor due to trace —DNA in the donor’s egg—in structures called mitochondria, for instance—that could affect the clone’s development. (In fact, there have been recent reports of human babies who have genetic material from three adults, due to a technique that uses healthy mitochondria from a donor’s egg to enhance fertility.) So, though Dolly resembled her DNA donor, other sheep that Wilmut and his colleagues have cloned vary in appearance and temperament from their DNA donors as well as from other clones developed from the same DNA.


It is also important to note that Dolly was born only after more than 200 other clones were spontaneously aborted or stillborn. Attempts to clone animals since have often resulted in severe birth defects—from dramatically increased birth size to enlarged organs to immune deficiencies. Going back to the blueprint analogy, Cornell professor and cloning expert Jonathan Hill adds, “It seems the cloned DNA is not only a ‘used’ blueprint but one that may have certain pages stuck together, making some of the details particularly hard to read.” As a result of these and other factors, many scientists—and politicians—believe there should be a ban on human cloning. Others are wary that such a ban might be too restrictive, since some techniques used in cloning are also used in other promising areas of science —including applications of IVF technology and stem cell research.


STEM CELL RESEARCH


CLONING AND STEM CELL RESEARCH ARE CONNECTED IN AT LEAST ONE important way. Every one of the trillions of cells in our bodies (including our eggs and sperm, which have but one set instead of two) contain the same DNA. The cells in your skin, for example, contain the same gene for produc-ing insulin as those in certain regions of your pancreas, but only the latter actually make the protein. Most of the genes in our cells are inactive, leaving only the very relevant ones to do their work. Though we know little about how this occurs, we do know that there is a period early in development when the cells have yet to begin the processes of determination and differentiation into blood, muscle or any other kind of cell, and all cells can still develop into any cell in the adult. In humans, this property—called pluripotency—is lost by the end of the second week after fertilization. Part of what made Wilmut’s success with Dolly so extraordinary was that he seems to have been able to revert an adult sheep cell back to its pluripotent state (though with all of the unexplained complications we’ve already detailed). Other techniques are being pursued for isolating adult stem cells—cells that are only partially differentiated—and reverting them to a pluripotent state, or nudging them to develop in particular directions. In the meantime, there is another source of pluripotent ce11s~ the embryo itself. Pluripotent cells from human embryos are the embryonic stem cells at the center of last summer’s debate.


Much of that continuing debate centers on the fact that human embryonic stem cells are obtained, almost exclusively, from embryos left over from IVF. Though propon -ents of research on them point out that they would be destroyed anyway, many opponents believe that these embryos, though composed of just a few dozen cells, are human lives, and so should be saved


The other reason that stem cells have burst into the news has to do with their excep-tional promise. Scientists have learned to culture human embryonic stem cells and allow them to divide and multiply, while preventing them from switching on or off any of their genes. By exposing these stem cells to different molecular compounds, they are trying to understand how that switching process works so that they can direct this cell to become a neuron, say, or that one to become a blood cell. (These two examples, in fact, are feats at which they have already had some measure of success.)


Eventually, some believe, we may be able to control the development of these pluripotent cells so that we can replace tissues damaged by disease or accident. Nerve cells damaged by Parkinson’s or spinal cord injury, for example, or heart tissue of cardiac patients, might ultimately be replaced by tissue grown from stem cells.


Some scientists see even the potential to create custom-made tissue by using stem cells that are exact matches to a particular person, thus obviating the greatest prob-lem in transplant surgery—rejection of the implant by the host’s immune system. “Therapeutic cloning,” as this procedure has been called, would involve inserting a patient’s own DNA into an egg and then prompting the cell and egg to fuse and start dividing, as was done in creating Dolly . Each cell in the resulting embryo, and thus its stem cells, would have exactly the same DNA as the patient, and tissues derived from these cells would match exactly the patient’s own tissues.


Along the wide spectrum of debate, there are those for whom embryonic stem cell research is acceptable as long as embryos are used with the consent of the egg and/ or sperm donors (or, in the case of therapeutic cloning, the sole DNA donor); there are those who believe it is acceptable as long as it is done with embryos that would be destroyed anyway; and there are those for whom destroying even these “extra” embryos is abhorrent, and creating embryos for research or therapy all the more so.


President Bush, in his August, 2000, address, announced that the federal government would fund research with human embryonic stem cells but only that which uses those “lines” (cells developed from the original stem cells of a single embryo) already in existence. The scientific community has argued (and the administration has conceded) that there are fewer lines developed for research than the more than 6o” the President mentioned in his speech. Those that do exist, they say, may be inappropriate for use in human therapies, because they have been cultivated in mouse-cell cultures and represent a very limited gene pool. Other critics of the President’s position point out that—as in many areas of research—curbing public funding does not mean that the research won’t go on, just that it will go on, unreg-ulated, under private sponsorship . Still others feel that the President was wrong to let any such research continue, let alone with public funding . Clearly, the debate isn’t ending any time soon.


We are often reminded that just because we can do something—such as exploit the latest technology—does not mean that we should. Jan Wilmut—a vocal opponent of human cloning despite (or perhaps because of) his work with animals—offers a complementary observation: “What is ‘natural,”’ he points out, “is not necessarily right, and what is ‘unnatural’ is not necessarily wrong.


It is always risky navigating uncharted territory. President Bush stated it adroitly, in August, when he said: “As we go forward, I hope we will always be guided by... ....both our capabilities and our conscience.



JAMES TREFIL, a professor of physics at George Mason University, is a frequent contributor                                    SMITHSONIAN Magazine (pgs. 38-46)

www.smithreader.com



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